Among the problems faced in certain types of drug therapy, including cancer chemotherapy and malaria drug therapy, is the phenomena of resistance to treatment regimens. The resistance means, for example, that cancerous tumors that responded well initially to a particular drug or drugs, later develop a tolerance to the drug(s). Drug resistance is the name given to the circumstance when a disease does not respond to a treatment drug or drugs. Drug resistance can be either intrinsic, which means the disease has never been responsive to the drug(s), or it can be acquired, which means the disease ceases responding to a drug or drugs to which the disease had previously been responsive. Multidrug resistance is a specific type of drug resistance that is characterized by cross-resistance of a disease to more than one functionally and/or structurally unrelated drugs. Multidrug resistance in the field of cancer, is discussed in greater detail in Kuzmich and Tew, “Detoxification Mechanisms and Tumor Cell Resistance to Anticancer Drugs,” particularly section VII “The Multidrug-Resistant Phenotype (MDR),” Medical Research Reviews, Vol. 11, No. 2, 185-217, particularly 208-213 (1991); and in Georges, Sharom and Ling, “Multidrug Resistance and Chemosensitization: Therapeutic Implications for Cancer Chemotherapy,” Advances in Pharmacology, Vol. 21, 185-220 (1990).
Treatment of drug and multidrug resistance typically involves the coadministration of a drug suitable for treatment of the disease and a compound which acts through various mechanisms to cause the drug suitable for treatment of a disease to begin and/or continue to function as a therapeutic agent.
U.S. Pat. No. 5,654,304 ('304), incorporated by reference herein, discloses a series of 10,11-(optionally substituted)methanodibenzosuberane derivatives useful in enhancing the efficacy of existing cancer chemotherapeutics and for treating multidrug resistance. (2R)-anti-5-{3-[4-(10,11-Difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride is disclosed in '304 and is currently under development as a pharmaceutical agent for the treatment of leukemia. WO00/75121 discloses Form I, a crystalline form of (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride.